Many pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystalline lattice. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice.
Polymorphs of a pharmaceutical solid may have different physical and solid-state chemical (reactivity) properties. These polymorphs differ in internal solid-state structure and, therefore, possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial and mechanical properties. These properties can have a direct impact on drug product quality/performance, including stability, dissolution and bioavailability.
The most stable polymorphic form of a drug substance is often used in a formulation because it has the lowest potential for conversion from one polymorphic form to another. On the other hand, metastable (a form other than the most stable form) and even amorphous forms may be chosen to enhance the bioavailability of the drug product. Amorphous form, being a disorganized solid mass, does not need to lose crystal structure before dissolution in the gastric juices, and thus often has greater bioavailability than a crystalline form.
Even if amorphous form is desirable for formulation, its preparation on industrial scale is often problematic. Many processes used to prepare amorphous form of an active pharmaceutical ingredient are not suitable for industrial scale. In Polymorphism in Pharmaceutical Sciences, Drugs and the Pharmaceutical Sciences, Vol. 95, the authors survey various processes for preparation of amorphous form, and list solidification of melt, reduction of particle size, spray-drying, lyophilization, removal of a solvent from crystalline structure, precipitation of acids and bases by change in pH and others as techniques employed to obtain amorphous form of an active pharmaceutical ingredient.
Many of these processes however are not practical on an industrial scale. For example, to obtain amorphous API by solidification of melt, the API has to be heated beyond its melting point, which may require expenditure of much energy, particularly when the API has a high melting point. Further, the high temperatures may chemically damage the API.
Another one of these processes, lyophilization, for example as shown in EP 1 384 721 and WO03/06595 for amorphous mupirocin calcium, is quite expensive process on large scale, and generally has limited capacity. Further, lyophilization with an organic solvent is often dangerous since it possesses a fire hazard.
Preparation of amorphous form of another active pharmaceutical ingredient, fexofenadine hydrochloride, by spray drying (atomization), is disclosed in WO 00/71124. According to Remington: The Science and Practice of Pharmacy, 19th Ed., vol. II, pg. 1627, spray drying consists of bringing together a highly dispersed liquid and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets. Spray-drying however is often limited to aqueous solutions unless special expensive safety measures are taken. Also in spite of the short contact time, certain undesirable physical and chemical characteristics of the emerging solids are in particular cases unavoidable. The turbulence present in a spray drier as a result of the moving air may alter the product in an undesirable manner. Modifications to the spray drying technique is disclosed in WO 03/063821 and WO 03/063822.
A need exists in the art for a process that allows for preparation of an amorphous form of an active pharmaceutical ingredient on an industrial scale.